Disorders of Phosphate Homeostasis

DISORDERS OF PHOSPHATE HOMEOSTASIS

Phosphate (P_i) combines with Ca²⁺ to form hydroxyapatite, the mineral component of bone and teeth and is also required for some enzymic activities, oxidative phosphorylation and the synthesis of 2,3-bisphosphoglycerate that regulates the dissociation of oxyhemoglobin , the excretion of H⁺ and for cell membrane integrity. The daily intake of P_i is about 40 mmol. The kidneys lose approximately 26 mmol daily and 14 mmol are lost in feces. The total body content of P_i in the average male is over 20 000 mmol (Figure 8.17) with 17 000 occurring in bone and 3000 in soft tissues, largely attached to lipids and proteins. Thus about 85% occurs in bone while the ICF and the ECF contain 15% and 0.1% respectively. The plasma concentration is about 1 mmol dm^–3. Approximately 80% of the plasma content occurs as free inorganic P_i, 15% is protein-bound and about 5% is complexed with Ca²⁺ and Mg²⁺. Parathyroid hormone (Figure 8.11) and the hormone, calcitriol, control the homeostasis of P_i; the former decreasing the reabsorption by the kidneys and reducing its plasma concentration, the latter stimulating P_i absorption in the GIT and increasing the concentration.

The reference range for total serum P_i is 0.8–1.4 mmol dm^–3 but a higher reference range applies in infancy and childhood. Hyperphosphatemia and hypophosphatemia are used to describe concentrations above and below the reference range respectively. Hypophosphatemia causes more damage than hyperphosphatemia but, fortunately, is less common.

Hyperphosphatemia may cause metastatic calcification, for example the deposition of calcium phosphate in soft tissues as the excess P_i precipitates with Ca²⁺ and causes hypocalcemia and tetany in affected patients. The commonest cause of hyperphosphatemia is renal failure where the GFR and P_i excretion decline. Hypoparathyroidism reduces renal excretion of P_i giving rise to hyperphosphatemia. In diabetic ketoacidosis , a deficiency of insulin prevents the uptake of P_i by cells leading to hyperphosphatemia. Other causes are an increased intake of P_i or its release from damaged cells in intravascular hemolysis. Indeed, any condition where there is increased turnover of cells, for example following treatment of malignant disease with chemotherapy, results in release of P_i during cell destruction. Excessive intake, either oral or intravenous, is a rare cause and is more likely when there is also renal failure as in pseudohypoparathyroidism where there is resistance by the kidneys to PTH that decreases their excretion of P_i. A delay in the separation of plasma or serum from blood before analysis for P_i or hemolysis of a blood sample prior to its analysis can indicate artefactual hyperphosphatemia but this does not reflect the true clinical situation.

A number of biochemical tests are useful when investigating hyperphosphatemia. These include determining the concentrations of P_i, Ca²⁺, urea and creatinine in serum and the concentration of P_i in urine. The following strategy has proved useful in investigating obscure causes of hyperphosphatemia. First, it is necessary to exclude artefactual causes. Secondly, serum concentrations of creatinine and urea should be determined to exclude renal failure. If the serum concentration of Ca²⁺ is normal or above reference values, vitamin D intoxication or untreated diabetes mellitus should be considered. Thirdly, if the plasma or serum concentration of Ca²⁺ is low, then hypoparathyroidism should be investigated. Finally, if the urinary concentration of P_i is low, then hypoparathyroidism is, again, a consideration, whereas a high urinary concentration indicates increased intake, malignancy or intravascular hemolysis. Patients with hyperphosphatemia are managed by treating the underlying cause wherever possible. The oral intake of aluminum, Ca²⁺ and Mg²⁺ salts may be used as these can bind P_i in the GIT reducing its absorption.

The clinical features of hypophosphatemia include paresthesiae, ataxia, coma, osteomalacia and muscle weakness. There may be increased susceptibility to infection possibly due to defective phagocytosis. The causes of hypophosphatemia are varied. Vitamin D deficiency results in a decreased synthesis of calcitriol and therefore decreased P_i absorption in the GIT. Increased renal loss of P_i may occur in primary hyperparathyroidism where increased secretion of PTH causes excessive renal loss of P_i. Certain diuretics that increase renal loss of P_i can cause hypophosphatemia. It may also occur during the recovery phase of diabetic ketoacidosis when patients are administered insulin, which promotes cellular uptake of P_i. Total body P_i may be depleted as a consequence of osmotic diuresis. There are a number of rare causes of hypophosphatemia. These include an inadequate dietary intake usually associated with parenteral nutrition, or when agents, such as aluminum hydroxide are used as antacids and prevent its absorption in the GIT, and in chronic alcoholics who have a complex and multifactorial condition with poor diet and reduced GIT absorption .

Determination of the serum concentrations of Pi and Ca2+ and the urinary concentration of Pi are useful in investigating hypophosphatemia. The following strategy may be used when its cause is not obvious. First, exclude causes such as alkalosis and chronic alcoholism. Secondly, a reduced urinary P_i suggests decreased dietary or parenteral intakes or increased cellular uptake, for example in insulin therapy. Thirdly, if the urinary concentration of P_i is above its reference range then excessive renal losses are occurring and the concentration of Ca²⁺ in the plasma or serum should be determined. If this is increased, then primary hyperparathyroidism or malignancy may be present. If, however, the concentration is low or normal, renal defects or inappropriate diuretic therapy are considerations. Hypophosphatemia should be managed by treating the underlying cause wherever possible. In some situations it may be necessary to administer oral or parenteral P_i.